Huntington's disease is a progressive neurodegenerative disorder that is associated with a CAG repeat expansion in the gene encoding huntingtin. We found that a 60-kDa protein was increased in Neuro2a cells expressing the N-terminal portion of huntingtin with expanded polyglutamine. We purified this protein, and, using mass spectrometry, identified it as p62, an ubiquitin-associated domain-containing protein. A specific p62 antibody stained the ubiquitylated polyQ inclusions in expanded polyglutamine-expressing cells, as well as in the brain of the huntingtin exon 1 transgenic mice. Furthermore, the level of p62 protein and mRNA was increased in expanded polyglutamine-expressing cells. We also found that p62 formed aggresome-like inclusions when p62 was increased in normal Neuro2a cells by a proteasome inhibitor. Knock-down of p62 does not affect the formation of aggresomes or polyglutamine inclusions, suggesting that p62 is recruited to the aggresome or inclusions secondary to their formation. These results suggest that p62 may play important roles as a responsive protein to a polyglutamine-induced stress rather than as a cross-linker between ubiquitylated proteins. Keywords: aggresome, Huntington's disease, p62, polyglutamine, proteasome inhibitor, RNA interference. Huntington's disease (HD) is an autosomal dominant neurodegenerative disorder with midlife onset that gives rise to progressive, selective neural cell death in the striatum associated with choreic movement and dementia (Vonsattel and DiFiglia 1998). The disease is associated with an unstable expansion of CAG repeats within the coding region of the gene encoding the protein huntingtin. Whereas wildtype chromosomes with a stable CAG repeat possess 6-34 repeats, more than 36 repeats result in an unstable, expanded, disease-associated allele. The mutation in huntingtin produces an expanded stretch of glutamine residues, and the mutant huntingtin aggregates with ubiquitylation, forming neuronal nuclear aggregates or inclusions and dystrophic neuritic inclusions in the HD cortex and striatum. Many observations have suggested that abnormal accumulation of the mutant protein is involved in pathogenesis of various neurodegenerative disorders, including polyglutamine diseases such as HD, by conferring a toxic gain of function (Zoghbi and Orr 2000).How inclusions contribute to altered cell function is not well understood but they could have a variety of effects on the regulation of gene transcription, protein interactions, and protein transport within the nucleus and cytoplasm. Various proteins, for example, ubiquitin, molecular chaperones, and components of the proteasome, co-localize with mutant proteins in the inclusions, which may result in the modification of important cellular functions. Recent studies suggest that cells avoid accumulating potentially toxic aggregates by using molecular chaperones to suppress aggregate formation and by using proteasomes to degrade misfolded proteins. This hypothesis is supported by the fact that chaperone Addres...

Malnutrition in the early stage has been reported as an independent predictor of survival in amyotrophic lateral sclerosis (ALS). We analyzed retrospectively the effect of variation of body mass index (BMI) on survival in ALS patients. In total, 77 consecutive ALS patients were enrolled from nine hospitals in Japan. Reduction rate of BMI was calculated from BMI before the disease onset and at the time of the first visit to each hospital. We analyzed the correlation between BMI reduction rate and total disease duration. Results showed that the median BMI reduction rate was 2.5 per year (interquartile range 1.3-3.8). The BMI reduction rate was significantly correlated with survival length (p <0.0001). There was also a significant difference in survival between ALS patients with a BMI reduction rate ≥ and < 2.5 (Kaplan-Meier survival analysis and the log-rank test, p < 0.0001; hazard ratio by the Cox model, 2.9816). In conclusion, faster reduction of BMI at the initial stage before the first visit to hospital predicts shorter survival length also in Japanese ALS patients.

Huntington disease is caused by polyglutamine (polyQ) expansion in huntingtin. Selective and progressive neuronal loss is observed in the striatum and cerebral cortex in Huntington disease. We have addressed whether expanded polyQ aggregates appear in regions of the brain apart from the striatum and cortex and whether there is a correlation between expanded polyQ aggregate formation and dysregulated transcription. We generated transgenic mouse lines expressing mutant truncated N-terminal huntingtin (expanded polyQ) fused with enhanced green fluorescent protein (EGFP) and carried out a high-density oligonucleotide array analysis using mRNA extracted from the cerebrum, followed by TaqMan RT-PCR and in situ hybridization. The transgenic mice formed expanded polyQ-EGFP fluorescent aggregates and this system allowed us to directly visualize expanded polyQ aggregates in various regions of the brain without performing immunohistochemical studies. We show here that polyQ-EGFP aggregates were intense in the hypothalamus, where the expression of six hypothalamic neuropeptide mRNAs, such as oxytocin, vasopressin and cocaine-amphetamine-regulated transcript, was down-regulated in the transgenic mouse brain without observing a significant loss of hypothalamic neurons. These results indicate that the hypothalamus is susceptible to aggregate formation in these mice and this may result in the downregulation of specific genes in this region of the brain.

The current study provides evidence that a gene on the SCA4 locus causes a pure cerebellar syndrome.

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